Special Feature: What’s New in Antibiotic Therapy for Acute Otitis Media
Special Feature
What’s New in Antibiotic Therapy for Acute Otitis Media
By Theodore C. Chan, MD, FACEP
Otitis media (OM) is the most frequently diagnosed childhood disease in the United States. Approximately one-half of all infants experience their first OM episode by 6 months of age, and at least 90% of children have one or more bouts by age 2. In 1995, the cost of OM treatment in this country was estimated at $3.8 billion annually.1,2
OM can be divided into several classifications. Acute otitis media (AOM) indicates the presence of a middle ear effusion (MEE) with acute inflammation of fewer than three weeks’ duration. OM with effusion (OME), previously known as serous, mucoid, nonsuppurative, or secretory OM, is the presence of MEE without signs of acute inflammation. Chronic OM implies a chronic middle ear infection with perforation of the tympanic membrane (TM) that results in drainage. Recurrent OM requires three or more AOM episodes within six months, or four or more within 12 months.
The incidence of AOM has risen markedly in the last two decades. Tympanostomy tube insertion rates have increased four-fold since the 1970s.2 This dramatic rise is in part due to the growing use of day care for younger children. Other risk factors include: age less than 2 years, male gender, passive tobacco smoke, bottle-feeding, craniofacial abnormalities, and family history. Despite the ubiquity of the disease, current management and treatment of AOM remains controversial. In particular, there is growing debate as to whether antibiotics are indicated and which regimen is most effective.
Are Antibiotics Necessary to Treat AOM?
While viruses are isolated in fewer than one-half of all cases, most episodes of AOM are initially precipitated by viruses.3 Viral infection of the upper respiratory epithelium leads to inflammation, bacterial colonization, and eustachian tube dysfunction. In turn, these factors cause the formation of MEE, inflammation, and bacterial invasion—all of which which precipitate AOM. As a result, AOM primarily is thought of as a bacterial illness requiring antibiotics. However, bacteria are isolated in only about 70% of cases.4 Spontaneous resolution occurs in anywhere from 50-80% of cases. As a result, many have questioned the utility of antibiotics.5 In fact, use of antibiotics varies greatly worldwide. While nearly all U.S. children receive antibiotics, as few as one-third are treated with antibiotics in parts of Europe.6 Large comparison studies assessing the efficacy of antibiotics suggest only marginal benefit in terms of cure rates and prevention of complications.6,7 In an analysis of trials involving more than 5400 patients, Rosenfeld reported that seven children would need to be treated in order to prevent one treatment failure.8 Twenty children would need antibiotics to reduce pain temporarily for one.9 Moreover, rates of vomiting, diarrhea, rashes, and other side effects are increased markedly.6
In many European countries, physicians have adopted a policy of "watchful waiting," in which early therapy is withheld for uncomplicated AOM. If symptoms persist beyond 24-72 hours, or if complications develop, antibiotics are then administered. Antibiotic use has been reduced by nearly two-thirds and there is evidence of decreased bacterial resistance in these regions.7 While "watchful waiting" has generally been restricted to children age 2 and older, there are some data suggesting that this practice may be safe and effective in younger children (6 months to 2 years).10 However, these studies must be interpreted with caution due to the wide variability in outcome parameters and inclusion criteria (such as the method of AOM diagnosis). Many of these investigations studied only short-term outcomes and did not assess for recurrent infections, hearing loss, or other long-term complications.
There is good historical evidence that antibiotics have had a tremendous beneficial impact. Complications, such as meningitis and mastoiditis, occurred in nearly 20% of children in the pre-antibiotic era. With the advent of antimicrobial therapy, this rate has dropped to as low as 1-3%.11 Moreover, reports in the mid-1990s of a rising incidence of mastoiditis in Europe have led to some concern.12 Finally, while comparative studies suggest that the impact may be modest, antibiotics do result in improved cure rates of up to 90-95% over observation alone.8 As a result, in this country, antibiotic therapy continues to be a mainstay of treatment for AOM.
Antibiotic Agent and Regimen: Which Is Best?
Therapy has focused on efficacy for the three main bacterial pathogens: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Standard-dose amoxicillin for 10 days has been considered first-line therapy for a long time. Alternatives have included trimethoprim-sulfamethoxazole, erythromycin-sulfisoxazole, and amoxicillin-clavulanate. The growing use of newer cephalosporins (e.g., cefaclor, cefuroxime, cefpodoxime, cefixime, cefprozil, loracarbef, and ceftriaxone), as well as the development of new macrolide antibiotics (e.g., azithromycin and clarithromycin) have led to a reconsideration of optimal therapy. These newer antibiotics often have advantages over standard amoxicillin in terms of ease of dosing, compliance, and administration.13
One of the chief advantages of the newer antibiotics is the potential for short-course therapy. Little data support the standard 10-day course, which has been carried over from penicillin therapy for streptococcal pharyngitis. Shorter three- to seven-day courses of antibiotics such as azithromycin and some cephalosporins (cefaclor, cefpodoxime, cefprozil), as well as single or three daily injections of ceftriaxone, have been studied and found to be highly efficacious.13-15
Studies comparing different antibiotics and short-course therapies must be interpreted cautiously. Because of the high spontaneous cure rate for uncomplicated AOM, it is easy to prove equivalence, but difficult to demonstrate clinical superiority of one regimen over another. As a result, in Rosenfeld’s analysis of 5400 patients, there was no clinical advantage with newer antibiotics when compared to standard amoxicillin.8 In addition, in many of the studies of short-course therapy, children at high risk for complicated infections were excluded, limiting applicability.
One argument for short-course therapy is the problem of resistance from selective antibiotic pressure. Increasing bacterial drug-resistance has caused concern that standard therapy may be inadequate and could lead to treatment failures and adverse outcomes. Concern has been greatest with regard to the dramatic rise of penicillin- and multidrug-resistant Streptococcus pneumoniae (DRSP), which has been reported at rates as high as 35% in certain regions.16 AOM from the pneumococcus, the most common bacterium isolated, remains the least likely to spontaneously resolve and most likely to develop complications.17
Despite emerging resistance (as many as 80-100% of Moraxella catarrhalis isolates are beta-lactam resistant), the rise in treatment failures has been less dramatic. In vitro resistance of MEE isolates does not invariably result in in vivo clinical treatment failure. Moreover, the most clinically recalcitrant cases occur in those in whom both bacteria and viral pathogens, rather than just resistant bacteria, are isolated from the MEE.18
New Antibiotic Recommendations
As a result of these concerns, the Centers for Disease Control and Prevention (CDCP) and the American Academy of Pediatrics (AAP), along with the DRSP Therapeutic Working Group of the CDCP, recently published guidelines for the use of antimicrobials for AOM.19,20
The CDCP-AAP guidelines support the routine use of antibiotics for AOM. However, in an effort to reduce selective antibiotic pressure, the group recommends that short-course therapy of 5-7 days be considered in children 2 years or older with uncomplicated AOM. Short-course therapy, however, was not recommended for children at increased risk of treatment failure (< age 2, TM perforation, or history of chronic or recurrent AOM).
Despite resistance concerns, amoxicillin remains the first-line antimicrobial agent. However, in order to increase middle ear antibiotic concentrations to combat DRSP, the CDCP-AAP guidelines recommended increasing the dose from the standard 40-45 mg/kg/d to 80-90 mg/kg/d (or 3-3.5 mg in adults). The use of "high-dose" amoxicillin was emphasized for regions in which DRSP prevalence is high, and also as an option for recurrent AOM or treatment failures. In addition, to improve compliance, high-dose amoxicillin can be administered twice daily.
Alternatives and second-line therapies included both standard and high-dose amoxicillin-clavulanate, though the dose should be calculated to limit clavulanate to less than 10 mg/kg to reduce the risk of gastrointestinal side effects. Newer formulations have reduced the dose of clavulanate to ease this concern. Of the extended cephalosporins, cefuroxime was noted to have excellent in vitro activity against the DRSP and other pathogens, but concerns were raised regarding palatability and compliance. While the working group had concerns regarding the activity of cefprozil and cefpodoxime, other investigators have argued that compliance and ease of dosing make these cephalosporins attractive.5
The group also recommended the use of single daily parenteral ceftriaxone in cases of treatment failure or when compliance was a concern. While some studies have suggested three daily injections are more efficacious than single-day treatment, the guidelines recommended an initial dose, followed by recheck in 24-48 hours. If symptoms have resolved, no further therapy is warranted. Otherwise, repeat dosing could be administered on the second and third days.21
Other investigators and the CDCP-AAP group expressed concern regarding the lack of in vivo and in vitro studies supporting the efficacy of other cephalosporins (cefaclor, cefixime, loracarbef, and ceftibuten).5,19,20 Because of growing pneumococcal resistance to trimethoprim-sulfamethoxazole, use should be limited to regions in which the drug is known to be effective. In addition, macrolides were not selected as initial therapy because of growing resistance of DRSP. Importantly, macrolide resistance is absolute and cannot be overcome by increased dosages. Despite these concerns, these antibiotics still may be considered, particularly for patients who are beta-lactam allergic.21
With changing resistance patterns and ongoing research, it is likely that optimal antimicrobial therapy for AOM will continue to evolve. There is growing evidence for both the efficacy and safety of quinolones in children. New antibiotics being developed, including ketolides and oxazolodinones, may play an important role in the future. Moreover, research on non-antibiotic therapies (such as oligosaccharides and xylitol that prevent bacterial colonization), as well as new prophylactics (like the pneumococcal vaccine and antiviral drugs), is promising, and may lead to a day when routine antibiotic therapy no longer is indicated definitively for AOM.22
References
1. Bosker G. Otitis media in children: Antimicrobial strategies for overcoming barriers to clinical care. Pediatr Emerg Med Rep 1997;2:13-16.
2. Daly KA. Clinical epidemiology of otitis media. Pediatr Infect Dis J 2000;19:S31-36.
3. Heikkinen T. Role of viruses in the pathogenesis of acute otitis media. Pediatr Infect Dis J 2000;19:S17-22.
4. Heikkinen T, Chonmaitree T. Increasing importance of viruses in acute otitis media. Ann Med 2000;32:157-163.
5. Aronovitz GH. Antimicrobial therapy of acute otitis media. Review of treatment recommendations. Clin Therapeutics 2000;22:29-39.
6. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-1529.
7. Froom J, Culpepper L, Jacobs M, et al. Antimicrobials for acute otitis media? A review from the international primary care network. BMJ 1997;315:98-102.
8. Rosenfeld RM, Vertrees JE, Carr J, et al. Clinical efficacy of antimicrobial drugs for acute otitis: Meta-analysis of 5400 children from 33 randomized trials. J Pediatr 1994;124:335-367.
9. Glasziou PP, Del Mar C, Hayem, et al. Antibiotics for acute otitis media in children. Cochrane Database Syst Rev 2000;2: CD000219.
10. Damoiseaux RAM, van Balen FA, Hoes AW, et al. Antibiotic treatment of acute otitis media in children under 2 years of age: Evidence based? Brit J Gen Prac 1998;48:1861-1864.
11. Bluestone CD. Clinical course, complications, and sequelae of acute otitis media. Pediatr Infect Dis J 2000;19:S37-46.
12. Hoppe JE, Koster S, Bootz F, et al. Acute mastoiditis—Relevant once again. Infection 1994;22:178-182.
13. Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, et al. Treatment of acute otitis media with a shortened course of antibiotics—A meta-analysis. JAMA 1998;279:1736-1742.
14. Cohen R, Levy C, Boucherat M, et al. Five vs. ten days of antibiotic therapy for acute otitis media in young children. Pediatr Infect Dis J 2000;19:458-463.
15. Leibovitz E, Piglansky L, Raiz S, et al. Bacteriologic and clinical efficacy of one-day vs. three-day intramuscular ceftriaxone for treatment of nonresponsive acute otitis media in children. Pediatr Infect Dis J 2000;19:1040-1045.
16. Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the U.S. N Engl J Med 2000;343:1917-1924.
17. Musher D, Dagan R. Is the pneumococcus the one and only in acute otitis media? Pediatr Infect Dis J 2000;19:399-400.
18. Chonmaitree T. Viral and bacterial interaction in acute otitis media. Pediatr Infect Dis J 2000;19:S24-30.
19. Dowell SF, Marcy SM, Phillips WR, et al. Otitis media—Principles of judicious use of antibicrobial agents. Pediatrics 1998;101:165-167.
20. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: Management and surveillance in an era of pneumococcal resistance—A report from the DRSP therapeutic working group. Pediatr Infect Dis J 1999;18:1-9.
21. Klein JO. Review of consensus reports on management of acute otitis media. Pediatr Infect Dis J 1999;18:1152-1155.
22. Klein JO. Management of otitis media: 2000 and beyond. Pediatr Infect Dis J 2000;19:383-387.
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